Your browser doesn't support javascript.
loading
Discovery of novel BTK inhibitors with carboxylic acids.
Gao, Xiaolei; Wang, James; Liu, Jian; Guiadeen, Deodial; Krikorian, Arto; Boga, Sobhana Babu; Alhassan, Abdul-Basit; Selyutin, Oleg; Yu, Wensheng; Yu, Younong; Anand, Rajan; Liu, Shilan; Yang, Chundao; Wu, Hao; Cai, Jiaqiang; Cooper, Alan; Zhu, Hugh; Maloney, Kevin; Gao, Ying-Duo; Fischmann, Thierry O; Presland, Jeremy; Mansueto, My; Xu, Zangwei; Leccese, Erica; Zhang-Hoover, Jie; Knemeyer, Ian; Garlisi, Charles G; Bays, Nathan; Stivers, Peter; Brandish, Philip E; Hicks, Alexandra; Kim, Ronald; Kozlowski, Joeseph A.
Affiliation
  • Gao X; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Wang J; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Liu J; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA. Electronic address: jian_liu@merck.com.
  • Guiadeen D; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Krikorian A; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Boga SB; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Alhassan AB; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Selyutin O; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Yu W; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Yu Y; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Anand R; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Liu S; WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China.
  • Yang C; WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China.
  • Wu H; WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China.
  • Cai J; WuXi PharmaTech Co. Ltd, 288 FuTe Zhong Road, No. 1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China.
  • Cooper A; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Zhu H; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Maloney K; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Gao YD; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Fischmann TO; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Presland J; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Mansueto M; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Xu Z; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Leccese E; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Zhang-Hoover J; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Knemeyer I; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Garlisi CG; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Bays N; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Stivers P; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Brandish PE; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Hicks A; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Kim R; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
  • Kozlowski JA; Department of Early Development and Discovery Sciences, MRL, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett ; 27(6): 1471-1477, 2017 03 15.
Article in En | MEDLINE | ID: mdl-28254166
ABSTRACT
We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.
Subject(s)
Key words
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Protein-Tyrosine Kinases / Carboxylic Acids / Protein Kinase Inhibitors / Drug Discovery Limits: Animals / Humans Language: En Year: 2017 Type: Article
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Protein-Tyrosine Kinases / Carboxylic Acids / Protein Kinase Inhibitors / Drug Discovery Limits: Animals / Humans Language: En Year: 2017 Type: Article